title: α-Bromophosphonate analogs of glucose-6-phosphate are inhibitors of glucose-6-phosphatase.
abstract: Glucose-6-phosphatase (G6Pase) is an essential metabolic enzyme that has upregulated activity in Type II diabetes. Synthetic analogs of the G6Pase substrate, glucose-6-phosphate (G6P), may provide new tools to probe enzyme activity, or lead to specific inhibitors of glycosylphosphatase enzymes. Here we have developed synthetic routes to a panel of non-hydrolyzable G6P analogs containing α-bromo, α,α-dibromo, and α-bromo-α,β-unsaturated phosphonates compatible with a carbohydrate nucleus. We confirm that these functionalities have potency as inhibitors of G6Pase in vitro, providing a series of new phosphate isosteres that can be exploited for inhibitor design.
authors.affiliation: Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
authors.forename: A Michael
authors.initials: AM
authors.lastname: Downey
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cairo
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D063065:Organophosphonates; D019298:Glucose-6-Phosphate; D005952:Glucose-6-Phosphatase
keywords: Glucose-6-phosphatase (G6Pase); Glucose-6-phosphate (G6P); Non-hydrolyzable phosphate isostere; α-Bromophosphonate